scholarly journals Potential therapeutic approaches for targeted inhibition of inflammatory cytokines following COVID-19 infection-induced cytokine storm

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Nelli Morgulchik ◽  
Foteini Athanasopoulou ◽  
Edmund Chu ◽  
Yoriko Lam ◽  
Nazila Kamaly
Keyword(s):  
Inflammatory Cytokines ◽  
Distress Syndrome ◽  
Multiorgan Failure ◽  
Cytokine Storm ◽  
Therapeutic Approaches ◽  
Global Pandemic ◽  
Blood Clots ◽  
Specific Manner ◽  
Targeted Inhibition ◽  
Pro Inflammatory Cytokines

Coronavirus disease 2019 (COVID-19) is a deadly respiratory disease caused by severe acute respiratory syndrome coronavirus 2, which has caused a global pandemic since early 2020 and severely threatened people's livelihoods and health. Patients with pre-diagnosed conditions admitted to hospital often develop complications leading to mortality due to acute respiratory distress syndrome (ARDS) and associated multiorgan failure and blood clots. ARDS is associated with a cytokine storm. Cytokine storms arise due to elevated levels of circulating cytokines and are associated with infections. Targeting various pro-inflammatory cytokines in a specific manner can result in a potent therapeutic approach with minimal host collateral damage. Immunoregulatory therapies are now of interest in order to regulate the cytokine storm, and this review will summarize and discuss advances in targeted therapies against cytokine storms induced by COVID-19.

scholarly journals The signal pathways and treatment of cytokine storm in COVID-19

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Lan Yang ◽  
Xueru Xie ◽  
Zikun Tu ◽  
Jinrong Fu ◽  
Damo Xu ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Inflammatory Cytokines ◽  
Multiorgan Failure ◽  
Significant Proportion ◽  
Treatment Strategies ◽  
Current Evidence ◽  
Signal Pathways ◽  
Type I ◽  
Cytokine Storm ◽  
Pro Inflammatory Cytokines

AbstractThe Coronavirus Disease 2019 (COVID-19) pandemic has become a global crisis and is more devastating than any other previous infectious disease. It has affected a significant proportion of the global population both physically and mentally, and destroyed businesses and societies. Current evidence suggested that immunopathology may be responsible for COVID-19 pathogenesis, including lymphopenia, neutrophilia, dysregulation of monocytes and macrophages, reduced or delayed type I interferon (IFN-I) response, antibody-dependent enhancement, and especially, cytokine storm (CS). The CS is characterized by hyperproduction of an array of pro-inflammatory cytokines and is closely associated with poor prognosis. These excessively secreted pro-inflammatory cytokines initiate different inflammatory signaling pathways via their receptors on immune and tissue cells, resulting in complicated medical symptoms including fever, capillary leak syndrome, disseminated intravascular coagulation, acute respiratory distress syndrome, and multiorgan failure, ultimately leading to death in the most severe cases. Therefore, it is clinically important to understand the initiation and signaling pathways of CS to develop more effective treatment strategies for COVID-19. Herein, we discuss the latest developments in the immunopathological characteristics of COVID-19 and focus on CS including the current research status of the different cytokines involved. We also discuss the induction, function, downstream signaling, and existing and potential interventions for targeting these cytokines or related signal pathways. We believe that a comprehensive understanding of CS in COVID-19 will help to develop better strategies to effectively control immunopathology in this disease and other infectious and inflammatory diseases.

scholarly journals COVID-19 Pathology on Various Organs and Regenerative Medicine and Stem Cell-Based Interventions

2021 ◽  
Vol 9 ◽  
Author(s):  
Babak Arjmand ◽  
Sepideh Alavi-Moghadam ◽  
Peyvand Parhizkar Roudsari ◽  
Mostafa Rezaei-Tavirani ◽  
Fakher Rahim ◽  
...  
Keyword(s):  
Stem Cell ◽  
Severe Acute Respiratory Syndrome ◽  
Inflammatory Cytokines ◽  
Systemic Inflammation ◽  
Multiple Organ ◽  
Cytokine Storm ◽  
Functional Impairments ◽  
Therapeutic Approaches ◽  
Novel Coronavirus ◽  
Pro Inflammatory Cytokines

Severe acute respiratory syndrome-coronavirus 2, a novel betacoronavirus, has caused the global outbreak of a contagious infection named coronavirus disease-2019. Severely ill subjects have shown higher levels of pro-inflammatory cytokines. Cytokine storm is the term that can be used for a systemic inflammation leading to the production of inflammatory cytokines and activation of immune cells. In coronavirus disease-2019 infection, a cytokine storm contributes to the mortality rate of the disease and can lead to multiple-organ dysfunction syndrome through auto-destructive responses of systemic inflammation. Direct effects of the severe acute respiratory syndrome associated with infection as well as hyperinflammatory reactions are in association with disease complications. Besides acute respiratory distress syndrome, functional impairments of the cardiovascular system, central nervous system, kidneys, liver, and several others can be mentioned as the possible consequences. In addition to the current therapeutic approaches for coronavirus disease-2019, which are mostly supportive, stem cell-based therapies have shown the capacity for controlling the inflammation and attenuating the cytokine storm. Therefore, after a brief review of novel coronavirus characteristics, this review aims to explain the effects of coronavirus disease-2019 cytokine storm on different organs of the human body. The roles of stem cell-based therapies on attenuating cytokine release syndrome are also stated.

scholarly journals Computational Identification of Potential Anti-Inflammatory Natural Compounds Targeting the p38 Mitogen-Activated Protein Kinase (MAPK): Implications for COVID-19-Induced Cytokine Storm

Biomolecules ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 653
Author(s):  
Seth O. Asiedu ◽  
Samuel K. Kwofie ◽  
Emmanuel Broni ◽  
Michael D. Wilson
Keyword(s):  
Molecular Docking ◽  
P38 Mapk ◽  
Inflammatory Cytokines ◽  
Binding Energies ◽  
Mitogen Activated Protein Kinase ◽  
Inflammatory Activity ◽  
Computational Techniques ◽  
Cytokine Storm ◽  
Anti Inflammatory ◽  
Pro Inflammatory Cytokines

Severely ill coronavirus disease 2019 (COVID-19) patients show elevated concentrations of pro-inflammatory cytokines, a situation commonly known as a cytokine storm. The p38 MAPK receptor is considered a plausible therapeutic target because of its involvement in the platelet activation processes leading to inflammation. This study aimed to identify potential natural product-derived inhibitory molecules against the p38α MAPK receptor to mitigate the eliciting of pro-inflammatory cytokines using computational techniques. The 3D X-ray structure of the receptor with PDB ID 3ZS5 was energy minimized using GROMACS and used for molecular docking via AutoDock Vina. The molecular docking was validated with an acceptable area under the curve (AUC) of 0.704, which was computed from the receiver operating characteristic (ROC) curve. A compendium of 38,271 natural products originating from Africa and China together with eleven known p38 MAPK inhibitors were screened against the receptor. Four potential lead compounds ZINC1691180, ZINC5519433, ZINC4520996 and ZINC5733756 were identified. The compounds formed strong intermolecular bonds with critical residues Val38, Ala51, Lys53, Thr106, Leu108, Met109 and Phe169. Additionally, they exhibited appreciably low binding energies which were corroborated via molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) calculations. The compounds were also predicted to have plausible pharmacological profiles with insignificant toxicity. The molecules were also predicted to be anti-inflammatory, kinase inhibitors, antiviral, platelet aggregation inhibitors, and immunosuppressive, with probable activity (Pa) greater than probable inactivity (Pi). ZINC5733756 is structurally similar to estradiol with a Tanimoto coefficient value of 0.73, which exhibits anti-inflammatory activity by targeting the activation of Nrf2. Similarly, ZINC1691180 has been reported to elicit anti-inflammatory activity in vitro. The compounds may serve as scaffolds for the design of potential biotherapeutic molecules against the cytokine storm associated with COVID-19.

scholarly journals Role of Inflammatory Cytokines in COVID-19 Patients: A Review on Molecular Mechanisms, Immune Functions, Immunopathology and Immunomodulatory Drugs to Counter Cytokine Storm

Vaccines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 436
Author(s):  
Ali A. Rabaan ◽  
Shamsah H. Al-Ahmed ◽  
Javed Muhammad ◽  
Amjad Khan ◽  
Anupam A Sule ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Inflammatory Markers ◽  
Therapeutic Drug ◽  
Molecular Pathways ◽  
Cytokine Storm ◽  
Immunomodulatory Drugs ◽  
Alveolar Cells ◽  
Systemic Complications ◽  
Anti Inflammatory ◽  
Pro Inflammatory Cytokines

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a severe pandemic of the current century. The vicious tentacles of the disease have been disseminated worldwide with unknown complications and repercussions. Advanced COVID-19 syndrome is characterized by the uncontrolled and elevated release of pro-inflammatory cytokines and suppressed immunity, leading to the cytokine storm. The uncontrolled and dysregulated secretion of inflammatory and pro-inflammatory cytokines is positively associated with the severity of the viral infection and mortality rate. The secretion of various pro-inflammatory cytokines such as TNF-α, IL-1, and IL-6 leads to a hyperinflammatory response by recruiting macrophages, T and B cells in the lung alveolar cells. Moreover, it has been hypothesized that immune cells such as macrophages recruit inflammatory monocytes in the alveolar cells and allow the production of large amounts of cytokines in the alveoli, leading to a hyperinflammatory response in severely ill patients with COVID-19. This cascade of events may lead to multiple organ failure, acute respiratory distress, or pneumonia. Although the disease has a higher survival rate than other chronic diseases, the incidence of complications in the geriatric population are considerably high, with more systemic complications. This review sheds light on the pivotal roles played by various inflammatory markers in COVID-19-related complications. Different molecular pathways, such as the activation of JAK and JAK/STAT signaling are crucial in the progression of cytokine storm; hence, various mechanisms, immunological pathways, and functions of cytokines and other inflammatory markers have been discussed. A thorough understanding of cytokines’ molecular pathways and their activation procedures will add more insight into understanding immunopathology and designing appropriate drugs, therapies, and control measures to counter COVID-19. Recently, anti-inflammatory drugs and several antiviral drugs have been reported as effective therapeutic drug candidates to control hypercytokinemia or cytokine storm. Hence, the present review also discussed prospective anti-inflammatory and relevant immunomodulatory drugs currently in various trial phases and their possible implications.

Montelukast - Its Immunomodulatory and Antiviral Action in COVID-19

2021 ◽  
Vol 8 (21) ◽  
pp. 1731-1732
Author(s):  
Prashant Ramesh Chakkarwar
Keyword(s):  
Tissue Factor ◽  
Inflammatory Cytokines ◽  
Factor Vii ◽  
Clotting Factor ◽  
Activate Factor ◽  
Cytokine Storm ◽  
Oak Ridge ◽  
Montelukast Sodium ◽  
Tnf Α ◽  
Pro Inflammatory Cytokines

Coronavirus disease-19 (COVID-19) is the deadliest pandemic that the whole world is facing today. COVID-19 is different from normal flu by its two lethal manifestations which includes deadly pneumonia which may lead to acute respiratory distress syndrome (ARDS) due to hyper-inflammation of alveolar tissues and pulmonary intravascular coagulopathy (PIC).1,2 It is noteworthy here to mention that both these lethal manifestations of COVID-19 are due to abnormally high levels of pro-inflammatory cytokines like interleukin (IL) - 1β, IL - 6, and tumour necrosis factor (TNF) - α, termed as “cytokine storm.”3,4 There is a certain link between pro-inflammatory cytokines like IL - 1β, IL - 6, and TNF - α and its pro-coagulatory influence on coagulation pathway mediated by tissue factor that binds and activate factor VII, leading to formation of tissue factor – VII a complexes which results in the activation of clotting factor X and IX.4 Recently the researchers in China and some European countries have found raised level of pro-inflammatory cytokines particularly IL - 6 in severe cases of COVID-19. They also found raised D-dimer, fibrinogen levels and prothrombin time in moderate to severe COVID-19 cases.5,6 Both of these lethal manifestations of COVID-19 – ARDS and PIC are linked to raised levels of pro-inflammatory cytokines, particularly, IL - 6. It is not very clear that the pro-inflammatory action of cytokines is mediated through leukotrienes as the biochemical assay for leukotrienes are not widely available but possibility of this probable mechanism cannot be ruled out. Hence, development of any molecule with ability to inhibit pro-inflammatory cytokines, particularly IL-6 may be able to tame the lethal nature of COVID-19, and may ultimately reduce the mortality of this deadly pandemic. Montelukast sodium is such molecule which has capacity to inhibit proinflammatory cytokines such as IL - 1β, IL - 6, and TNF - α.7 Montelukast sodium is leukotriene receptor antagonist that inhibits the cysteinyl leukotriene type-1 receptor. Leukotrienes modulate the production of pro-inflammatory cytokines.8 Its antagonist action on leukotriene receptors can inhibit the production of these pro-inflammatory cytokines. Even recent in silico study by Jacobson at Oak Ridge National Lab, was found that excess bradykinin production may be responsible for pulmonary, cardiac, neurological and nephrological lethal manifestations of COVID-19.9 Crimi et al.10 already found that Montelukast is effective to control bradykinin induced bronchoconstriction. Thus, theoretically, montelukast seems to be best molecule to deal with deadly manifestation of COVID-19 even if we go by cytokine storm hypothesis or bradykinin hypothesis.

scholarly journals The Use of Dupilumab in Atopic Dermatitis During Coronavirus Disease-19 Era – A Review

2020 ◽  
Vol 8 (T1) ◽  
pp. 399-407
Author(s):  
Laura Pauline Kosasih
Keyword(s):  
Atopic Dermatitis ◽  
Distress Syndrome ◽  
Multiple Organ ◽  
Cytokine Storm ◽  
T Helper ◽  
Immunomodulatory Treatment ◽  
Global Pandemic ◽  
Common Causes ◽  
Th 1 ◽  
Vast Range

The global pandemic of coronavirus (CoV) d0isease 2019 (COVID-19), caused by severe acute respiratory syndrome CoV (SARS-CoV 2), has been a challenging event for every individual. It is known that COVID-19 may exhibit a vast range of symptoms ranging from mild to severe. Acute respiratory distress syndrome (ARDS) and multiple organ failure are the most common causes of death in COVID-19 cases [3]. Accumulating evidence shows that T-helper type (Th-1) inflammation cascade plays a major role in COVID-19 pathogenesis. It is proposed that aberrant immune reaction, or known as cytokine storm, is one of the main causals of ARDS in COVID-19 case, while dupilumab, the first Food and Drug Administration-approved immunomodulatory treatment for atopic dermatitis, is known for its effectiveness in suppressing the Th-2 inflammation pathway. It is postulated that both types of inflammation can cross-regulate each other. Therefore, some may believe that the regression of Th-2 cascade may upregulate the Th-1 cascade, leading to an exaggerated cytokine storm. This hypothesis leads to the uncertainty of the safety of continuing this modality during the pandemic.

Histone Deacetylase Inhibitor SAHA Reduces Cytokine Storm and Facilitates Induction of Chimerism When Combined with Anti-CD3 mAb in Conditioning of Recipients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2168-2168
Author(s):  
Nainong Li ◽  
Dongchang Zhao ◽  
Chunyan Zhang ◽  
Chia-Lei Lin ◽  
Mark Kirschbaum ◽  
...  
Keyword(s):  
T Cells ◽  
Inflammatory Cytokines ◽  
Histone Deacetylase Inhibitor ◽  
Low Dose ◽  
Conditioning Regimen ◽  
Serum Levels ◽  
Cytokine Storm ◽  
Spleen Cells ◽  
Deacetylase Inhibitor ◽  
Pro Inflammatory Cytokines

Abstract Donor T cell-mediated graft versus leukemia (GVL) and graft versus autoimmunity (GVA) plays a critical role in the treatment of hematological malignancies and refractory autoimmune diseases using allogeneic hematopoietic cell transplantation (HCT). However, graft versus host disease (GVHD) remains a major obstacle in classical HCT, where recipients are usually conditioned with total body irradiation or high dose chemotherapy. We have recently reported a radiation-free and GVHD preventive anti-CD3-conditioning regimen, which allows donor CD8+ T cells to facilitate engraftment and mediate GVL without causing GVHD (PNAS, 2007 and J. I. 2007). In order to promote the clinical application of the anti-CD3-conditioning regimen, we need to overcome the cytokine storm that causes flu-like syndrome in patients after anti-CD3 mAb injection and reduce the required donor bone marrow cell dose. Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, was reported by others to induce apoptosis of human T cell lymphoma cell lines and to reduce serum levels of pro-inflammatory cytokines in HCT recipients. Therefore, we tested whether conditioning with a combination of anti-CD3 and SAHA can reduce the cytokine storm caused by anti-CD3 and reduce the resistance of engraftment mediated by residual host T cells. Accordingly, titrated dose of SAHA (0.125–8 μM) were added to cultures of BALB/c spleen cells stimulated with plate-bound anti-CD3. We found that SAHA augmented apoptosis of anti-CD3 activated T cells in a dose-dependent manner. Although low-dose SAHA (0.125–0.25 μM) did not augment apoptosis, it rendered the residual live T cells partially unresponsive. At the same time, SAHA significantly reduced the pro-inflammatory cytokines (IL-2, IFN-γ, TNF-α, and IL-6) in the culture supernatants. Similarly, in vivo treatment with anti-CD3 and low-dose SAHA (40 μg/g) led to significant reduction of serum levels of those cytokines and partial unresponsiveness of the residual host T cells. Finally, conditioning with combined anti-CD3 and SAHA (40 μg/g) induced complete chimerism without GVHD in 12/12 of old BALB/c as well as in 8/8 of old autoimmune lupus NZB/NZW F1 recipients after two injections of BM cells (2 ×106/g) and CD4+ T-depleted spleen cells (4 ×106/g), although conditioning with anti-CD3 alone did not induce any chimerism (0/8). The chimeric NZB/NZW F1 recipients showed complete reversal of autoimmune glomerulonephritis and proteinuria. These results indicate that SAHA can not only reduce cytokine storm but also facilitate engraftment when combined with anti-CD3 for conditioning of recipients. This radiation free and GVHD preventive conditioning regimen may provide a novel approach for clinical HCT.

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